Fc receptors (FcR) are a family of highly related receptors that are specific for the Fc portion of immunoglobulin (Ig). These receptors have major roles in normal immunity and resistance to infection and provide the humoral immune system with a cellular effector arm. Receptors have been defined for each of the immunoglobulin classes and as such are defined by the class of Ig of which they bind (i.e. Fc gamma receptor (FcγR) bind gamma immunoglobulin (IgG), Fc epsilon receptor (FcεR) bind epsilon immunoglobulin (IgE), Fc alpha receptor (FcαR) bind alpha immunoglobulin (IgA)). Among the FcγR receptors, three subfamily members have been defined; FcγRI, which is a high affinity receptor for IgG; FcγRII, which are low affinity receptors for IgG that avidly bind to aggregates of immune complexes; and FcγRIII, which are low affinity receptors that bind to immune complexes. These receptors are highly related structurally but perform different functions. The structure and function of FcγRII is of interest because of its interaction with immune complexes and its association with disease.
FcγR are expressed on most hematopoietic cells, and through the binding of IgG play a key role in homeostasis of the immune system and host protection against infection. FcγRII is a low affinity receptor for IgG that essentially binds only to IgG immune complexes and is expressed on a variety of cell types including, for example monocytes, macrophages, neutrophils, eosinophils, platelets and B lymphocytes. FcγRII is involved in various immune and inflammatory responses including antibody-dependent cell-mediated cytotoxicity, clearance of immune complexes, release of inflammatory mediators and regulation of antibody production. The binding of IgG to a FcγR can lead to disease indications that involve regulation by FcγR. For example, the autoimmune disease thrombocytopenia purpura involves tissue (platelet) damage resulting from FcγR-dependent IgG immune complex activation of platelets or their destruction by FcγR+ phagocytes. In addition, various inflammatory diseases are known to involve IgG immune complexes (e.g. rheumatoid arthritis, systemic lupus erythematosus), including type II and type III hypersensitivity reactions. Type II and type III hypersensitivity reactions are mediated by IgG, which can activate either complement-mediated or phagocytic effector mechanisms, leading to tissue damage.
The elucidation of the protein structure of FcγRIIa, FcεRI, or indeed any FcR is of importance in the formulation of therapeutic and diagnostic reagents for disease management. Until the discovery of the present invention, the structure and resulting mechanism by which FcγRIIa regulates immune responses was unknown. Thus, despite the general multifunctional role of FcγRIIa, development of useful reagents for treatment or diagnosis of disease was hindered by lack of structural information of the receptor. The linear nucleic acid and amino acid sequence of FcγRIIa have been previously reported (Hibbs et al. Proc. Natl. Acad. Sci. USA, vol. 85, pp. 2240-2244, 1988). Mutagenesis studies to identify regions of human FcγRIIa (Hulett et al., Eur. J. Immunol., vol. 23, pp. 40-645, 1993; Hulett et al., J. Biol. Chem., vol. 69, pp. 15287-15293 1994; and Hulett et al., J. Biol. Chem., vol. 270, pp. 21188-21194, 1995), human FcγRIIIb (Hibbs et al., J. Immunol., vol. 152, p. 4466, 1994; and Tamm et al., J. Biol. Chem., vol. 271, p. 3659, 1996) and mouse FcγRI (Hulett et al., J. Immunol., vol. 148, pp. 1863-1868, 1991) have defined important regions of IgG binding to the FcγR. Information based on linear sequences, however, cannot accurately predict three dimensional structure of the protein and its functional domains. Huber et al. (J. Mol. Biol., vol. 230, pp. 1077-1083, 1993) have described crystal formation of neonatal rat Fc receptor protein (FcRn). Burmeister et al. (Nature, vol. 372, pp. 336-343, 1994; and Nature, vol. 372, pp. 379-383, 1994) have described the structure of FcRn crystals. FcRn, however, is closely related to major histocompatability protein complex and not related to the leukocyte FcγR family by function or structure. Thus, the protein structure of FcRn is not predictive of the FcR structure of the present invention.
FcεR are expressed on mast cells, and through the binding of IgE, trigger an inflammatory immune response which is primarily due to the release of inflammatory mediators upon degranulation of the mast cell (e.g., histamine and serotonin). Release of these mediators causes localized vascular permeability and increase in fluids in the local tissues, including an influx of polymorphonuclear cells into the site. Thus, binding of IgE to an FcεRI can lead to disease indications that involve discharge of fluids from the gut and increased mucus secretion and bronchial contraction, such indications typically being associated with diseases involving allergic inflammation.
Therefore, the elucidation of protein structure of FcεRI is of importance in the formulation of therapeutic and diagnostic reagents for disease management, and in particular, for the management of diseases related to allergic inflammation and other Th2-based immune responses. As for the FcγR described above, the linear nucleic acid and amino acid sequences of human FcεRI have been previously reported (Kochan et al., 1998, Nuc. Acid. Res. 16:3584). Until the discovery of the present invention, however, the structure and resulting mechanism by which FcεR regulates immune responses was unknown. Thus, despite the knowledge of the general action of FcεRI, the development of useful reagents for treatment or diagnosis of disease, such as diseases associated with allergic inflammation, was hindered by lack of structural information of the receptor.
Because FcR are involved in a variety of biological mechanisms, there is a need for compounds which affect the binding of immunoglobulins to FcR. There is also a need for using such compounds to treat a variety of illnesses.